Recently, enantiomerically pure compounds are taking on significance. Specifically in pharmaceutical industry, enantiomerically pure compounds often show low side effects and high titer over racemic compounds, and thus have very high availability. Conventional methods of organic synthesis for obtaining pure enantiomers use often chiral adjuvants, which can be obtained from natural products, or resolution of racemic compounds. The chiral adjuvants should be used in an equivalent amount rather than a catalytic amount, and are naturally occurring compounds, whereby they are structurally limited. The method of resolving racemates using resolving agents means that the undesired enantiomers are discarded, and has drawbacks of low yield and waste.
Oda, et al. (J. Oda, J. Chem. Soc. Perkin Trans I. 1987, 1053) reported a method for preparing chiral hemiesters comprising performing a ring-opening reaction of cyclic acid anhydrides using (+)-cinchonine, of cinchona alkaloids, in a catalytic amount (10 mol %). However, said method has problems that the reaction time is as long as 4 days and the enantioselectivity is low (up to 69% ee).
Bohn, et al. (C. Bolm, J. Org. Chem. 2000, 65, 6984) described an efficient method for preparing chiral hemiesters having the enantioselectivity of up to 91% ee comprising subjecting 10 mol % of qunidine to a ring-opening of cyclic acid anhydrides. But, there are problems that 1 equivalent of expensive pempidine must be used and that the reaction must be performed at −55° C. for up to 6 days.
Furthermore, L. Deng, et al. reported, in KR Patent No. 10-0769381, a method of using modified bis-cinchona alkaloids, for example, (DHQD)2AQN as a catalyst, among method for preparing chiral hemiesters using organocatalysts (Y. Chen, S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2000, 122, 9542-9543). If said catalyst is used, the reaction may be successfully completed due to high enantioselectivity. However, there is a problem that it is industrially applied, since the very long reaction time (up to 140 hours) is required, the amount of the catalyst is relatively high, and the low temperature (−20° C. to −40° C.) must be maintained to obtain high enantioselectivity. Furthermore, a problem has been reported, in which quantity synthesis of catalyst is very difficult (Y. Ishii, et al., Organic Process Research & Development, 2007, 11, 609-615).
To obtain chiral hemesters having high enantioselectivity, the existing synthetic methods have a drawback that the reaction should be performed at low temperature for a long time. Therefore, it is required to develop more efficient catalysts and methods for preparing the same.